CA2590843A1 - Novel hydantoin derivatives as metalloproteinase inhibitors - Google Patents

Abstract

The invention provides compounds of formula (I): wherein R1, R2, A, A1 and B
are as defined in the specification; processes for their preparation;
pharmaceutical compositions containing them; a process for preparing the pharmaceutical compositions; and their use in therapy. The compounds are useful as MMP inhibitors.

Description

COMPOUNDS
The present invention relates to novel hydantoin derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
Metalloproteinases are a superfamily of proteinases (enzymes) whose numbers in recent years have increased dramatically. Based on structural and functional considerations these enzymes have been classified into families and subfamilies as described in N.M. Hooper (1994) FEBS Letters 354:1-6. Examples of metalloproteinases include the matrix metalloproteinases (MMPs) such as the collagenases (MMP1, MMP8, MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase (MMP12), enamelysin (MMP19), the MT-MMPs (MMP14, MMP 15, MMP 16, MMP 17); the reprolysin or adamalysin or MDC family which includes the secretases and sheddases such as TNF converting enzymes (ADAM10 and TACE);
the astacin family which include enzymes such as procollagen processing proteinase (PCP);
and other metalloproteinases such as aggrecanase, the endothelin converting enzyme family and the angiotensin converting enzyme family.

Metalloproteinases are believed to be important in a plethora of physiological disease processes that involve tissue remodelling such as.embryonic development, bone formati6n and uterine remodelli.n.g during menstruation. This is based on the abili-ty of the metalloproteinases to cleave a broad range of matrix substrates such as collagen, proteoglycan and fibronectin. Metalloproteinases are also believed to be important in the processing, or secretion, of biological important cell mediators, such as tumour necrosis factor (TNF); and the post translational proteolysis processing, or shedding, of biologically important membrane proteins, such as the low affinity IgE receptor CD23 (for a more complete list see N. M. Hooper et al., (1997) Biochem. J. 321:265-279).
Metalloproteinases have been associated with many diseases or conditions.
Inhibition of the activity of one or more metalloproteinases may well be of benefitin these diseas-es oy_ conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout),,inflammation of the gastro-intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema, dermatitis); in tumour metastasis or invasion; in disease associated with uncontTolled degradation of the extracellular matrix such as. osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget's disease); in diseases associated with aberrant angiogenesis; the enhanced collagen reinodelling associated with diabetes, periodontal disease (such as gingivitis), corneal ulceration, ulceration of the skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; demyelinating diseases of the central and peripheral nervous systems (such as multiple sclerosis); Alzlieimer's disease;
extracellular matrix remodelling observed in cardiovascular diseases such as restenosis and atheroscelerosis; asthma; rhiuzitis; and chronic obstructive pulmonary diseases (COPD).
MMP 12, also known as macrophage elastase or nietalloelastase, was initially cloned in the mouse by Shapiro et al [1992, Journal of Biological Chemistry 267: 4664] and in man by the same group in 1995. MMP12 is preferentially expressed in activated macrophages, and has been shown to be secreted from alveolar macrophages from smokers [Shapiro et al, 1993, Journal of Biological Cheinistiy, 268: 23824] as well as in foam cells in atherosclerotic lesions [Matsuinoto et al, 1998, Ain. J. Pathol. 153: 109]. A
mouse model of COPD is based on challenge of mice with cigarette smolce for six months, two cigarettes a day six days a week. Wild-type mice developed pulmonary emphysema afl:er this treatment. When MMP12 knock-out mice were tested in this model they developed no significant emphysema, strongly indicating that MMP12 is a key enzyme in the COPD
pathogenesis. The role of MMPs such as MMP12 in COPD (emphysema and bronchitis) is discussed in Anderson and Shinagawa, 1999, Current Opinion in Anti-inflammatory and Immunomodulatory Investigational Drugs 1 1: 29-38. It was recently discovered that smoking increases macrophage infiltration and macrophage-derived MMP- 12 expression in human carotid artery plaques Kangavari [Matetzky S, Fishbein MC et al., Circulation 102: 18 36-39 Suppl. S, Oct 31, 2000].

MMP9 (Gelatinase B, 92kDa Ty_peIV_Colla~enase; 92kDa Gelatinase) is a secreted protein _ which was first purified, then cloned and sequenced, in 1989 [S.M. Wilhelm et al (1989) J. Biol. Chem. 264 29 : 17213-17221; published erratum in J. Biol. Chem.
(1990) 265 36 : 22570]. A recent review of MMP9 provides an excellent source for detailed information and references on this protease: T.H. Vu & Z. Werb (1998) (In:
Matrix Metalloproteinases, 1998, edited by W.C. Parks & R.P. Mecham, pp. 115 - 148, Academic Press. ISBN 0-12-545090-7). The following points are drawn from that review by T.H. Vu & Z. Werb (1998).

The expression of MMP9 is restricted normally to a few cell types, including trophoblasts, osteoclasts, neutrophils and macrophages. However, the expression can be induced in these same cells and in other cell types by several mediators, including exposure of the cells to growth factors or cytokines. These are the same mediators often implicated in initiating an inflammatory response. As with other secreted MMPs, MMP9 is released as an inactive Pro-enzyme which is subsequently cleaved to form the enzymatically active enzyme. The proteases required for this activation in vivo are not known. The balance of active MMP9 versus inactive enzyme is furth.er regulated in vivo by interaction with TIMP-1 (Tissue Inhibitor of Metalloproteinases -1), a naturally-occurring protein. TIMP- 1 binds to the C=tenninal region of MMP9, leading to inhibition of the catalytic domain of MMP9. The balance of induced expression of ProMMP9, cleavage of Pro- to active and the presence of TIMP-1 combine to determine the amount of catalytically active MMP9 wliich is present at a local site. Proteolytically active MMP9 attacks substrates which include gelatin, elastin, and native Type IV and Type V collagens; it has no activity against native Type I collagen, proteoglycans or laminins.

There has been a growing body of data implicating roles for MMP9 in various physiological and pathological processes. Physiological roles include the invasion of embryonic trophoblasts through the uterine epithelium in the early stages of embryonic implantation; some role in the growth and development of bones; and migration of inflammatory cells from the vasculature into tissues.

MMP9 release, measured using enzyme immunoassay, was significantly enhanced in fluids and in AM supernantants from untreated asthmatics compared with those from other populations [Am. J. Resp. Cell & Mol. Biol., Nov 1997, 17 (5):583-591]. Also, increased MMP9 expression has been observed in certain other pathological conditions, thereby implicating MMP9 in disease processes such as COPD, arthritis, tumour metastasis, Alzheimer's disease, multiple sclerosis, and plaque rupture in atherosclerosis leading to acute coronary conditions such as myocardial infarction.

A number of metalloproteinase inhibitors are known (see, for example, the reviews of MMP inhibitors by Beckett R.P. and Whittalcer M., 1998, Exp. Opin. Ther.
Patents, 8 3:259-282; and by Whittaker M. et al, 1999, Chemical Reviews 99(9):2735-2776).
WO 02/074767 discloses hydantoin derivatives of formula s R4 Y1 R

R5 A z m kNH
X
y2 that are useful as MMP inhibitors, particularly as potent MMP12 inhibitors.
We now disclose a further group of hydantoin derivatives that are inhibitors of metalloproteinases and are of particular interest in inhi.biting MMPs such as MMP12 and MMP9. The compounds of the present invention have beneficial potency, selectivity and/or pharmacolcinetic properties. The compounds of the present invention are withi.n the generic scope of WO 02/074767 but are of a type not specifically exemplified therein.

In accordance with the present invention, there are provided compounds of fonnula (I) R' A' ~ ~ - N\S. --NH -(I) wherein Rl represents H, halogen, CF3 or CH2CN;

R2 represents C 1 to 3 allcyl; and A, Al and B eacli independently represent CH or N;
and pharmaceutically acceptable salts thereof The compounds of formula (1) may exist in enantiomeric forms. It is to be understood that all enantiomers, diastereomers, racemates and mixtures thereof are included witliin the scope of the invention.

Compounds of formula (I) may also exist in various tautomeric forms. All possible tautomeric forms and mixtures thereof are included within the scope of the invention.
In one embodiment, Ri represents chloro.

In one embodiment, Rl represents CF3.

In one embodiment, R2 represents methyl or ethyl. In one embodiment, R2 represents methyl.

In one embodiment, A and Al each represent N. In another embodiinent, A
represents N
and Al represents CH. In another embodiment, A and Al each represent CH.

In one embodiment, B represents N. In another embodiment, B represents CH.

In one embodiment, Rl represents CF3; R2 represents methyl or ethyl; A and Al each represent N; and B represents CH.

s In one embodiment, Rt represents CF3; R2 represents methyl or ethyl; A and Al each represent N; and B represents N.

In one embodiment, R1 represents chloro; R2 represents methyl or ethyl; A
represents N
and A1 represents CH; and B represents N.

In one einbodiment, Ri represents chloro; R2 represents methyl or ethyl; and A, A1 and B
each represent CH.

Unless otherwise indicated, the term "C 1 to 3 allcyP" referred to herein denotes a straight or is branched chain alkyl group having from 1 to 3 carbon atoms.. Examples of such groups include methyl, ethyl, n-propyl and i-propyl.

Unless otherwise indicated, the term "halogen" referred to herein denotes fluoro, chloro, bromo and iodo.
Examples of compounds of the invention include:
(5S)-5-methyl-5-( { [6-[2-(trifluoromethyl)pyrimidin-5-yl]-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl }methyl)imidazolidine-2,4-dione;
(5,S)-5-({ [6-(4-chlorophenyl)-3,4-dihydroisoquinolin-2(1.H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;
{4-[2-( { [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl} sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]phenyl}acetonitrile;
(5S')-5-methyl-5- { [(6-pyridin-3-yl-3,4-dihydroisoquinolin-2(1fl)--- --- -- ---yl~sulfony-I]methyl~iriiidazolidine-2,4-dione;

(5S)-5-( { [6-(4-chlorophenyl)-3,4-dihydro-2,7-naphthyridin-2( lH)-yl]sulfonyl }methyl)-5-methylimidazolidine-2,4-dione;
and pharmaceutically acceptable salts thereof.

Each exemplified compound represents a particular and independent aspect of the invention.

The compounds of formula (I) may exist in enantiomeric forms. Therefore, all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope of the invention.
The various optical isomers may be isolated by separation of a racemic inixture of the compounds using conventional techniques, for example, fractional crystallisation, or HPLC.
Alternatively the optical isomers may be obtained by asymmetric synthesis, or by synthesis from optically active starting materials.

Where optically isomers exist in the compounds of the invention, we disclose all individual optically active forms and combinations of these as individual specific embodiments of the invention, as well as their corresponding racemates.

Preferably the compounds of formula (I) have (5S)-stereochemistry as shown below:

A~ p R' K B ~ N~ ~ =,,,, NH

0 0 N~

Where tautomers exist in the compounds of the invention, we disclose all individual tautomeric forms and combinations of these as individual specific embodiments of the invention.

The present invention includes compounds of formula (I) in the form of salts.
Suitable salts include those formed with organic or inorganic acids or organic or inorganic bases. Such salts will normally be pharmaceutically acceptable salts although non-pharmaceutically acceptable salts may be of utility in the preparation and purification of particular compounds. Such salts include acid addition salts such as hydrocliloride, hydrobromide, citrate, tosylate and maleate salts and salts formed with phosphoric acid or sulphuric acid.
In another aspect suitable salts are base salts such as an alkali metal salt, for example, sodium or potassium, an alkaline earth metal salt, for example, calcium or magnesium, or an organic amine salt, for example, triethylamine.
Salts of compounds of formula (I) may be formed by reacting the free base or anotlier salt thereof with one or more equivalents of an appropriate acid or base.

The compounds of fonnula (I) are useful because they possess phaYmacological acivity in animals and are thus potentially useful as pharmaceuticals. In particular, the compounds of the invention are metalloproteinase inhibitors and may, thus be used ir1 the treatment of diseases or conditions mediated by MMP 12 and/or MMP9 such as asthina, rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis (such as rheumatoid arthritis and osteoarthritis), atherosclerosis and restenosis, cancer, invasion and metastasis, diseases involving tissue destruction, loosening of hip joint replacements, periodontal disease, fibrotic disease, infarction and heart disease, liver and renal fibrosis, endometriosis, diseases related to the weakening of the extracellular matrix, heart failure, aortic aneurysms, CNS related diseases such as Alzheimer's disease and multiple sclerosis (MS), and haematological disorders.

In general, the compounds of the present invention are potent inhibitors of MMP9 and MMP12. The compounds of the present invention also show good selectivity with respect to a relative lac-k of inhibition of various other MMPs such as MMP14.

Accordingly, the present invention provides a compound of foimula_(I),or a_ pharmaceutically acceptable salt thereof, as hereinbefore defined for use in therapy.

In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.

In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for use in the treatinent of diseases or conditions in which inhibition of MMP12 and/or MMP9 is beneficial.

In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt tliereof, as hereinbefore defined in the manufacture of a medicament for use in the treatment of inflammatory disease.

In another aspect, the invention provides the use of a coinpound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for use iri the 'treatment of an obstructive airways disease such as asthma or COPD.

In another aspect,, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in the manufacture of a medicament for use in the tireatment of rheumatoid arthritis, osteoartluitis, atherosclerosis, cancer or multiple sclerosis.

In the context of the present specification, the term "therapy" also includes "prophylaxis"
unless there are specific indications to the contrary. The terms "therapeutic"
and "therapeutically" should be construed accordingly.

Prophylaxis is expected to be particularly relevant to the treat_m.ent of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in guestion_ Persons at risk of developi__g_ad?articular disease or condition generally iuiclude those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

The invention fin=ther provides a method of treating a disease or condition in which 5 inhibition of MMP12 and/or MMP9 is beneficial which comprises administering to a patient a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof as hereinbefore defined.

The invention also provides a method of treating an obstructive airways disease, for 10 example, asthma or COPD, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder to be treated. The daily dosage of the compound of formula (1)/salt (active ingredient) may be in the range from 0.001 mg/lcg to 75 mg/lcg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary.
Typically unit dosage forms will contain about 1 mg to 500 mg of a. compound of this invention.

The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably fiom 0.10 to 70 %w, of active ingredient, and, from 1 to 99.95 %w, more preferably from 30 to 99.90 %w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition. Conventional procedures for the selection and preparation of suitable phaYmaceutical formulations are described in, for example, "Pharmaceuticals -The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

Thus, the present invention also provides a phannaceutical coinposition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical coinpositions of this invention may be administered in a standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal' or rectal administration or by inhalation.
For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emu.lsibns, creams;'ointments; gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.

In addition to the con-ipounds of the present invention the pharrnaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more diseases or conditions referred to hereinabove such as "Symbicort" (trade mark) product.

The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which, comprises:
a) reaction of a compound of formula (II) .

12 PCT iSE 2005 / o 0 19 1~
O

L S NH
OO N~
H
(II) wherein R2 is as defined in formula (1) and L1 represents a leaving group, with a compound of formula (111) (or a salt thereof) ~ I
A~

B~ NH
(III) wherein Rl, A, A and B are as defmed in formula (1); or b) reaction of a compound of formula (V) R Z O
O p B~ 10 ~S NH
LG H --~

(V) wherein R2 and B are as defined in formula (1) and LG is a leaving group; with a boronic - acid der-ivative-of-form.ula -WI)---R~ A~

~
A \ I
B(OR)Z
(XII) wherein Rl, A and A1 are as defined in formula (7); or c) reaction of a compoun&of formula (IX) A
I I
.A

(IX) wherein Rl, R2, A, A1 and B are as defined in formula (1); with ammonium carbonate and potassium cyanide;
and optionally thereafter forming a phannaceutically acceptable salt thereof.

In the above process (a), suitable leaving groups Li include halo, particularly chloro or trifluoromethylsulfonate. The reaction is preferably performed in a suitable solvent optionally in the presence of an added base for a suitable period. of time, typically 0.5 to 16 h, at ambient to reflux temperature. Typically solvents such as N,N-dimethylformamide, pyridine, tetrahydrofu.ran, acetonitrile, N-methylpyrrolidine or dichloromethane are used.
When used, the added base may be an organic base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine or pyridine, or an inorganic base such as an alkali metal carbonate. The reaction is typically conducted at ambient temperature for 0.5 to 16 h, or until completion of the reaction has been achieved, as determined by -------- chromatographic or spectroscopic methods. Reactions of sulfonyl halides with varioub primary and secondary amines are well lcnown in the literature, and the variations of the conditions will be evident for those slrilled in the art.

Sulfonylchlorides of formula (II) wherein L1 represents chloro and R2 represents Me are disclosed in WO 02/074767 and references cited therein. Corresponding compounds wherein R2 represents C1 to 3 alkyl may be prepared using analogous methods.

Suitable processes for the preparation of compounds of formula (I) are described in a retrosyntlietic way in Scheme 1.

Scheme 1 R\,pI R~pi p ~ / I p ~ I (RO)ze~~~'~
B\ N%\' 1 O ~ g\ I N~S/ g~ ' N~PO
0 0 R2 //\\
(IXa-c) M-0 o O
(VIIIa-c) R*pI R' 'pl Rpr g~ N~S/,r \~ ~ B~ I NH ~ g\ I N~etl (1) a/\aR' H
(Illa-c) (IVno) V ~.
LG / I o ~ LG / LG

//\\ lta O O H
(Va-c) (Vlflc) (VIIa-c) R~ p~~S/ Y p' Y
o\ORH~'. p~ LG \ B(GR)2 4t) (X[) 01) In Scheme 1, protecting groups (PG) can be either carbamates (e.g. tert-butoxycarbamate), amides (e.g. trifluoroacetyl) or allVl (e.g. tert-butyl or benzyl). Leaving groups (LG) can be either chloride, bromide, iodide or trifluoromethylsulfonate. In the palladium-catalysed Suzuki couplings, either boronic acids or pinacolboronates may be used.
Intermediate (IVa-c) can be prepared by standard Suzuki coupling (Chenz. Rev. 1995, 95, 2457) between an electrophile (VIIa-c) and a boron reagent (Xll), or the other way around, between an 5 electrophile (XI) and a boron reagent (VIIla-c). The latter can be obtained from (VIIa-c) using standard Miyaura conditions (J. Org. Chefn.1995, 60, 7508-7510).
Deprotection of (1Va-c) either by hydrogen chloride in metlianol (PG = tert-butoxycarbonyl) or refluxing 1-chloroethyl chloroformate/ refluxing methanol (PG = ter=t-butyl or berizzyl) (Synlett. 1993, 195-196) gives amine (IIIa-c) as a hydrochloride salt. The free base can be obtained by 10 treatinent of (Illa-c) with base and extraction with an organic solvent such as ethyl acetate or toluene. Reacting (Illa-c) either as a salt or base in a suitable solvent (e.g. acetonitrile, tetrahydrofuran, N-methylpyrrolidine or NN-dimethylfoilnamide) with the sulfonyl chloride (II) in the presence of a tertiary amine (e.g. triethylamine, pyridine or N,N-diisopropylethylamine) for 0.5 to 16 hours produces compounds of formula (I).
An alternative route to compounds of formula (I) from intermediate (Illa-c) via methanesulfonamide (Xa-c) and ketone (IXa-c) has been previously described (WO
02/074767). Briefly, treatment of (IIIa-c) witli, methansulfonyl chloride and a tertiary amine (e.g. triethylamine, pyridine or.N,N-diisopropylethylamine) in a suitable solvent (e.g. dichloromethane or tetrahydroffaran) produces the methansulfonamide (Xa-c) which in turn can be transformed into the ketone (IXa-c) using standard procedures.
Heating ketone (IXa-c) with ammonium carbonate and potassiuin cyanide in 50% aqueous ethanol in a sealed vial at 80-90 C for 1 to 5 hours gives a racemic hydantoin that can be resolved by chiral chromatography (e.g. on OD-H with 100% ethanol).
In a third route, intermediate (VIIa-c) is deprotected as described above to give amine (VIa-c) as a hydrochloride salt. The free base can be isolated by treatment with base and extraction with an organic solvent e.g. etliyl acetate or toluene. Reacting (VIa-c) either as a salt or base in a suitable solvent (e.g. acetonitrile, tetrahydrofuran, N-methylpyrrolidine or N,N-dimethylformamide) with sulfonyl chloride (lI) in the presence of a tertiarv amine (e.g. triethylamine, pyridine or N,N-diisopropylethylamine) for 0.5 to 16 hours produces chiral sulfonamide (Va-c). The latter can be coupled with boron reagent (XII) using standard Suzuld conditions to give compounds of foi7nula (I).

Intermediates (VIIa-b) are conveniently prepared using the following methods.
The 1,2,3,4-tetrahydroisoquinoline intermediate (Vlla) Methods for the synth.esis of 1,2,3,4-tetrahydroisoquinolines are well lcnown in the literature. The classical route is the Pomeranz-Fritz reaction of benzaldehydes with a diacetal protected aminoacetaldehyde (Org. React. 1951, 6, 191) yielding the isoquinoline nucleus which upon catalytical reduction gives 1,2,3,4-tetrahydro-isoquinolines. Another route is the Bischler-Napieralsld reaction (Org. React. 1951, 6, 74) of a carbamate of 2-phenylethanamines with phosphoryl chloride in refluxing toluene or xylenes.
Reduction of the resulting cyclic benzamide with lithiuin aluminium hydride in tetrahydrofuran (1.
Med. Chem. 1987, 30(12), 2208-2216) or diborane in tetrahydrofuran (J. Med.
Chenz.
1980, 23(5), 506-511) affords the 1,2,3,4-tetrahydroisoquinoline. A variation of the Bischler-Napieralski reaction is the Pictet-Spengler synthesis (Org. React.
1951, 6, 151). In this reaction amides, carbamates or sulfonamides of 2-phenylethanaYnines are heated with paraformaldehyde and strong proton acids (e.g. trifluoroacetic acid, sulfiu7c acid) or Lewis acids in a solvent (e.g. dichloromethane, toluene, formic acid) to give the 1,2,3,4-tetrahydroisoquinoline in a single step (Tetrahedron 2002, 58(8), 1471-1478).
Scheme 2 Br /~ a, b r Br / Br / d Br W"COOBu-t \ HtTz \ I NICOCF\ I ~~ Route A (+ B-Br-isomer) VIIn 03 and 131 = CH
and LG = Br) Reagents:
a) (CF3CO)2O, Et3N; +4 C. b) (HCHO),,, H2SO4, HOAc; RT. c) NaBH4, E?OH; RT or NHj (conc), EIOH, heat d) (t-BuOCO),O, Et3N, DCNd, RT.

Preferably the 1,2,3,4-tetrahydroisoquinoline intermediate (VIIa) is synthesised by Route A shown in Scheme 2. This route is a Friedel-Craft-type reaction of N-[2-(3-bromophenyl)ethyl]-2,2,2-trifluoroacetamide with formaldehyde and sulfuric acid in acetic acid (Tetrahedron Lett. 1996, 3 7(31), 5453-5456) giving a mixture of the 6-bromo- and 8-bromoisomer in a ratio of 3 to 1. Replacement of the trifluoroacetamide group with a BOC-group gives (Vlla). The regioisomers are not conveniently separated at this stage.

The 1,2,3,4-tetrahydro-2,7-naphthyridine intermediate CVllb) In contrast to the 1,2,3,4-tetrahydroisoquinolines, there are rather few examples of synthetic methods for 1,2,3,4-tetrahydro-2,7-naphthyridines in the literature.
One importa.nt method to prepare 1,2,3,4-tetrahydro-2,7-naphthyridine is the regio-selective catalytic reduction of 2,7-napllthyridine (Eur. J. Med. Chena. Ther. 1996, 31(11), 875-888).
The synthesis of 2,7-naph.thyridine and some derivatives thereof has been described in the literature. One classical route involves several steps and starts with the acid catalysed condensation of malononitrile with diethyl 1,3-acetonedicarboxylate (J. Chein.
Soc. 1960, 3513-3515; see also J. Het.erocycl. Chern. 1970, 7, 419-421). A slightly different route to 2,7-naphthyridine involves oxidation of 4-formyl-2,7-naphth.yridine to give 2,7-naphthyridine-4-carboxylic acid followed by decarboxylation (Syntlzesis 1973, 46-47).
A completely different method is based on the internal Diels-Alder reaction of N-(ethoxycarbonyl)-N-(but-3-ynyl)amino-methylpyrazine and gives a mixture of 1,2,3,4-tetrahydro-2,7-naphthyridine and 5,6,7,8-tetrahydro-1,7-naphthyridine after hydrolysis of the carbamate group (WO 02/064574).

Scheme 3 Route B
SiMe~
Me0 / a, b Meo /II e MeO d Me0 N,, 0 Nz i 0 i0 N, A, N
Teo h xo , g xo ~ f Meo N\ NIN~ I N. N~ NH N, NH
COOBu-t COOBu-[
xHBr Reagents~--a) LiCH}NCH2CH,N(CH}; Z, THF, -70 C, b) n-BuLi in he:canes, -70 C, then I,. c) TMS-acetylone, PdCI,(PPh3)2, CuI, Et3N, THF, 60 C.
d) 7 M NH3, EtOH, 80 C. o)Hõ PtOõ HOAc. f) 48"/u HBr (aq), 120 C. g) (BOC)2O1 Et}N, H,O, THF. h) TEi0, PhMe, 30% P3P04.

Preferably the 1,2,3,4-tetrahydro-2,7-naphthyridine inteimediate (Vllb) can be synthesised as shown in Schemes 3 and 4. In Route B, commercially available 6-methoxynicotinaldehyde is treated successively with the lithium salt of NN,N'-trimethylethylenediamine, then n-BuLi in hexanes and finally iodine to afford the 4-iodo-6-methoxynicotinaldehyde (cf. Tetrahedron Lett. 1993, 34(39), 6173-6176). The iodo compound is coupled with trimethylsilylacetylene under usual Sonagashira-Hagihara conditions (Synthesis 1980, 627-630) al.ld the resulting 6-methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde is condensed with ammonium hydroxide in ethanol to give 3-methoxy-2,7-naphthyridine (Synthesis 1999, 2, 306-311).
Regioselective catalytical reduction (cf. Eur. J. Med. Chern. Ther. 1996, 31(11), 875-888) affords .6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine. Demethylation and N-protection with BOC-anh.ydride and finally treatment of the resulting tert-butyl 6-hydroxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate with triflic anhydride in a two-phase system gives (Vllb).

Scheme 4 Roure C

Me0 / Me0 b Ma0 c Me0 / ,0 a N~ I ~O - - N\ I N' Bu-t i IIu-i d Tf0 f HO e Me0 ~- E
~ ~ I rl.
Bu-t Bu-[ Bu-t Reagents:
a) n-BuLi, THF, -70 C then DMF, -70~C to RT. b) t-BuNHz, DCM, 3A mol. sieves.
e) Li-TMP, -200C then DMF, -20 to -10"C.
d) Ns13HrCN, MeOH, HOAc; RT. e) 48% HBr (aq), re[lux; work-up with KZCO3 (sq).
f) TfzO, pyridinc +4 C.

In Route C, commercially available 5-bromo-2-methoxy-4-methylpyridine in anliydrous _ tetrahydrofuran is metallated with n_BuLia.nd thentreatedwithN, N-climethylformauaide to afford 6-methoxy-4-methylnicotinaldehyde. This was converted to the tert-butylimine with tert-butylamine in dichloromethane. Metallation with lithiuin 2,2,6,6-tetramethylpiperidide (Li-TMP) (cf. J. Org. Che a.1993, 58, 2463-2467) and addition of N,N-dimethylformamide affords the iminoacetaldehyde which is reduced with sodium cyanoborohydride in methan.ol to give 2-tert-butyl-6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine. Cleavage of the methyl group witli refluxing 48% hydrobromic acid and treatment with triflic anhydride in the presence of base gives (VIIb) protected as the tert-butylamine.

It will be appreciated by those skilled in the art that in the processes of the present invention certain potentially reactive functional groups such as hydroxyl or amino groups in the starting reagents or intennediate compounds may need to be protected by suitable protecting groups. Thus, the preparation of the compounds of the invention may involve, at various stages, the addition and removal of one or more protecting groups.

Suitable protecting groups and details of processes for adding and removing such groups are described in'Protective Groups in Organic Chemistry', edited by J.W.F.
McOmie, Plenum Press (1973) and'Protective Groups in Organic Synthesis', 3rd edition, T.W.
Greene and P.G.M. Wuts, Wiley-Interscience (1999).

The compounds of the invention and intermediates thereto may be isolated from their reaction mixtures and, if necessary further purified, by using standard techniques.

The present invention will now be further explained by reference to the following illustrative examples.

General Methods 'H NMR and 13C NMR spectra were recorded on a Varian Inova 400 MHz or a Varian Altercury-VX 300 MHz inst_riament. The central peaks of chloroform-d (6H 7.27 ppm), dimethylsulfoxide-d6 (SH 2.50 ppm), acetonitrile-d3 (SH 1.95 ppm) or methanol-d4 (SH 3.31 _ 30 __ _ppm) were used_as intemal.references_Column_chromatography_was._carried_out using_ silica gel (0.040-0.063 mm, Merck) with a slight over-pressure (0.2-0.4 bars) applied on the column. A Kromasil KR-100-5-C1$ column (250 x 20 mm, Akzo Nobel) and mixtures of acetonitrile/water with 0.1 % TFA at a flow rate of 10 mL/min were used for preparative HPLC. Unless stated otherwise, starting materials were commercially available.
All solvents and commercial reagents were of laboratory grade and were used as received. The organic phases from extractions were dried over anhydrous sodium sulfate if not stated 5 otherwise. Organic phases or solutions were concentrated by rotary evaporation. Yields were not optimised.

The following method was used for LC-MS anal sis:
Instrument Agilent 1100; Column Waters Synzrnetry 2.1 x 30 mm; Mass APCI; Flow rate io 0.7 mL/min; Wavelength 254 or 220 nm; Solvent A: water + 0.1% TFA; Solvent B:
acetonitrile + 0.1% TFA ; Gradient 15-95%/B 2.7 min, 95% B 0.3 The following method was used for GC-MS analysis:
Instrument Hewlett Paclcard 5890 Series II; Column Agilent HP-5 (30 in x 0.32 mm ID);

15 Mass selective detector Hewlett Packard 5971 Series ; Pressure 55 kPa He;
Oven program 100 C (3 min) to 300 C, 25 C/

Abbreviations:
20 BOC-anhydride di-tert-butyl dicarbonate n-BuLi n-butyl lithium DCM dichloromethane DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethylsulfoxide EtOAc ethyl acetate EtOH ethanol GC-MS gas chromatography- mass spectrometry -LDA lithium diisopropylarnide MeOH methanol LC-MS liquid chromatography- mass spectroscopy PdCl2 x dppf 1,1'-bis(diphenylphosphino)ferrocene palladium(II)dichloride RT room temperature, normally 20 to 22 C
TEA triethylamine THF tetrahydrofuran TBME tert-butyl methyl ether TFA trifluoroacetic acid Triflic anhydride trifluoromethanesulfonic anhydride (Tf20) Example 1 (5S)-5-Methyl-5-({[6-[2-(trifluoromethyl)pyrimidin-5-yl]-3,4-dih droisoquinolin-2(1H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione F
F
F ~ ~N
N~
H
N1~0 N
O H O

[(4S)-4-Methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.0295 g, 0.13 mmol) in dry THF (0.60 mL) was added dropwise to a stirTed solution of 6-[2-(trifluoromethyl)pyrimidin-5-yl]-1,2,3,4-tetrahydroisoquinoline (0.039 g, 0.14 mmol), DIPEA (0.034 mL, 0.20 mmol) and dry THF (0.60 mL) at ice-bath temperature.
After the addition was complete the solution was stirred at RT for 2 h and then taken up in water-brine and extracted twice with EtOAc. The combined organic phases were washed with brine, dried, filtered and concentrated to give a crude product. Purification by preparative HPLC afforded 0.050 g (76%) of the title compound as a white solid.
LC-MS m/z 470 (M+l);

1H NMR (CD3CN) S 9.19 (s, 214), 8.51 (br s, 1H), 7.62 (s, 1H), 7.61 (dd, 1H), 7.36 (d, 1H), 6.33 (br s, 114), 4.51 (s, 2H), 3.57 (t, 2H), 3.52 (d, 1H), 3.42 (d, 1H), 3.04 (t, 2H) and 1.48 (s, 3H) ppm.
The starting materials were prepared as follows:
6-[2-(Trifluorometh~)pyrimidin-5-yl]-1,2,3,4-tetrahydroisoquinoline tert-Buty16-[2-(trifluorom ethyl)pyrimidin-5-yl]-3,4-dihydroiso quinoline-2 (1H)-carboxylate (0.051 g, 0.13 mmol) was stirred in TFA (1.0 mL) and DCM (1.0 mL) at RT
overnight, then concentrated twice, the second time with added toluene (5 mL), to afford the trifluoroacetate salt.
LC-MS rizlz 280 (M+1);

1H NMR (CD3CN) S 9.25 (s, 2H), 7.73 (m, 2H), 7.44 (d, 1H), 4.45 (s, 2H), 3.56 (t, 2H) and 3.24 (t, 2H) ppm.
The crude product was taken up in 1M sodium carbonate solution (10 mL) and extracted twice with EtOAc. The combined organic phases were washed witli brine, dried, filtered and concentrated to give 0.039 g (100%) of the title product as a white solid.

2-(Trifluorometh&I)pyriinidin-5-yl trifluoromethanesulfonate Triflic anhydride (13.9 g, 85 nnnol) in dry DCM (70 mL) was added slowly to an ice-cold solution of 2-(trifluoromethyl)pyrimidin-5-ol (13.9, 85 mmol) (US 4,558,039), DIPEA (16 1s mL, 93 mmol) and dry DCM ( 260 mL) at such a rate that the temperature was kept between 4 C and 6 C. After the addition was complete, the solution was'stirred for 2.5 h at 4 C and then allowed to warm to RT. Water (50 mL) and 1M phosphoric acid (4.5 mL) were added and the phases were washed and separated. The organic phase was washed successively with water and saturated sodium bicarbonate, dried, filtered and carefully concentrated by rotary evaporation (pressure 300-400 mbar). The dark-red oil was purified by column chromatography with EtOAc-heptanes (1:8 through 1:4) as eluent to give 22.5 g (90%) of the title product as a colourless oil that crystallised in the cold.
Alternatively, the product could be purified by distillation, b.p. 75-77 C/10 mbar.

H NMR (CDC13) 6 8.90 (s, 2H) ppm.
ter t-Buty16-[2-(trifluoromethXl)p, rimidin-5-yl]-3,4-dihydroisoquinoline-2 carbox. late A 4:1 mixture (0.10 g, 0.28 mmol) of ter=t-butyl6-(4,4,5,5-tetramethyl-1,3,2-d.ioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and tert-butyl8-(4,4,5,5-tetramethyl---so 1~3,2=dioxaborolan=2=y1)=3,4=dihydroisoquinoline=2(11~-carboxylate, 2-(trifluoromethyl)pyrimidin-5-yl trifluoromethanesulfonate (0.083 g, 0.28 mmol), PdC12 x dppf (0.0048 g), 2M sodium carbonate (1.1 mL), toluene (4.0 mL) and EtOH (1.0 mL) was purged with dry argon for ten minutes then heated in a sealed vial at 81 C
for 6 h. The black solution was filtered through glass-wool, taken up in water-brine and washed twice with EtOAc. The combined organic phases were dried, filtered and concentrated with silica (5 g). Column chromatography with EtOAc-heptanes (1:8 through 1:5) gave 0.051 g (48%) of the title product as white solid.
LC-MS rrr/z 380 (M+1);

1H NMR (CDC13) 8 9.06 (s, 2H), 7.44 (dd, 1H), 7.38 (br s, 1H), 7.30 (d, 1H), 4.66 (s, 2H), 3.71 (t, 214), 2.95 (t, 214), and 1.51 (s, 9H) ppm.

tert-Buty16-(4 4 5 5-tetramethyl-1 3 2-dioxaborolan-2-yl)-3 4-dihydroisoquinoline-2(1H) carbox late A 3:1 mixture (0.49 g, 1.6 mmol) of teNt-butyl6-bromo-3,4-dihydroisoquinoline-2(1H)-1s carboxylate and tert-butyl8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate, bis(pinacolato)diborane (0.45 g, 1.8 mmol), PdC12 x dppf (0.039 g, 0.048 mmol), potassiuin acetate (0.48 g, 4.8 mmol) and DMF (8.0 mL) was heated at 81 C
overnight. The solvent was evaporated, the residue taken up in water-brine and washed twice with EtOAc. The organic phase was dried, filtered and concentrated.
Column chromatography with EtOAc-heptanes (1:10 through 1:4) gave 0.24 g of a 4:1 niixture of the title product and tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2( lH)-carboxylate.

1H NMR (CDC13) S 7.62 (d, 1H), 7.60 (s, 1H), 7.13 (d, 1H), 4.59 (s, 2H), 3.64 (t, 2H), 2.85 (t, 2H), 1.50 (s, 9H) and 1.35 (s, 12H) ppm (6-isomer).

1H NMR (CDC13) 8 7.69 (d, 1H), 7.24-7.14 (m, 214), 4.88 (s, 214), 3.64 (t, 2H), 2.85 (t, 214), 1.50 (s, 9H) and 1.35 (s, 12H) ppm (8-isomer).

tert-Butyl 6-bromo-3,4-dihydroisoguinoline-2(1H)-carbox vlate 6-Bromo-2-(trifluoroacetyl) 1,2,3,4-tetrahydroisoquinoline was prepared in two steps from [2-(3-bromophenyl)ethyl]amine (4.0 g, 20 mmol) following the procedure of Stokker (Tetrahedron Lett. 1996, 3 7(31), 5453-5456). Column chromatography with EtOAc-heptanes (1:10 through 1:6) gave 2.3 g (7.5 mmol) of a 3:1 mixture of 6-bromo-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline and 8-bromo-2-(trifluoro-acetyl)-1,2,3,4-tetrahydroisoquinoline.

iH NMR (CDC13) S 7.62 (d, 1H), 7.60 (s, 1H), 7.13 (d, 1H), 4.59 (s, 2H), 3.64 (t, 2H), 2.85 (t, 2H) and 1.50 (s, 9H) and 1.35 (s, 12H) ppm (6-isomer).

iH NMR (CDC13) 8 7.69 (d, 1H), 7.24-7.14 (m, 2H), 4.88 (s, 2H), 3.64 (t, 2H), 2.85 (t, 2H) and 1.50 (s, 9H) and 1.35 (s, 12H) ppm (8-isomer).
The above material was stirred with absolute EtOH (100 mL) and 25% ammonium hydroxide (10 mL) at 60 C for 4 h. More 25% ammonium hydroxide (15 mL) was added and stirring continued at RT overnight. The volatiles were evaporated to leave the crude amine as a white solid.
LC-MS m/z 212, 214 (M+l ).
Dry THF (50 mL) and DIPEA (1.3 mL, 7.5 mmol) were added followed by BOC-anhydride (1.8 g, 8.2 nunol). The mixture was stirred at RT overnight. The volatiles were evaporated and the residue was taken up in water. The pH was adjusted to 2 with 1M
phosphoric acid and the product was extracted twice with EtOAc. The conibined organic phases were washed with brine made slightly alkaline with saturated sodium bicarbonate, dried, filtered and concentrated. The crude product was purified by column chromatography with EtOAc-heptanes (1:50 through 1:20) to give 2.24 g (96%) of a 3:1 mixture of the title product and teNt-butyl8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate.
LC-MS mlz 256, 258 (M-56);

iH NMR (CDC13) S 7.31 (dd, 1H), 7.30 (br s, 1H), 6.98 (d, 1H), 4.52 (s, 2H), 3.63 (t, 2H), 2.81 (t, 2H) and 1.50 (s, 9H) ppm (6-isomer .

1H NMR (CDC13) S 7.42 (dd, 1H), 7.12-7.01 (m, 214), 4.55 (s, 2H), 3.64 (t, 211), 2.84 (t, 2H) and 1.51 (s, 9H) ppm (8-isomer).

Example 2 (5S)-5-({F6-(4-Chlorophenyl)-3,4-dih droisoquinolin-2(1H)-_ - --------yl] sulfoUl} methyl)-5 -meth=ylimi dazolidine-2,4-dione ci /
o H
N, i0 N
oS~.u H

(5S)-5- { [(6-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}-5-methyl-imidazolidine-2,4-dione (0.016 g, 0.040 mmol), 4-chlorophenylboronic acid (0.0072 g, 5 0.045 mmol), PdC12 x dppf (0.0030 g), 2M sodium carbonate (0.15 mL), toluene (0.80 mL) and EtOH (0.20 mL) were stirred in a sealed vial at 95 C for 17 h. The solvent was evaporated and the residue was tal(en up in water. The solution was acidified with 10%
HOAc to pH 6 and then extracted twice with EtOAc. The combined organic phases were washed with brine-saturated sodium bicarbonate, dried, filtered and concentrated to give a 10 crude product.
LC-MS n2/z 434 (M+1).
Purification by preparative HPLC afforded 0.0080 g (46%) of the title compound as a white solid.

1H NMR (CD3CN) S 8.53 (br s, 1H), 7.62 (m, 2H), 7.46 (m, 4H), 7.23 (d, 1H), 6.34 (br s, 15 1H), 4.45 (s, 214), 3.53 (m, 2H), 3.49 (d, 1H), 3.39 (d, 1H), 2.99 (m, 2H) and 1.46 (s, 3H) ppm=

The compounds of Examples 3 and 4 were prepared using the general method of Example 2.

Example 3 14-F2-({r(4S)-4-Methyl-2,5-dioxoimidazolidin-4-yl]methyllsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yllphenLI} acetonitrile N

N, 1~0 O H
OS....a N 0 11_ H
White solid.

LC-MS nZ/z 439 (M+1);

iH NMR (CD3CN) S 8.61 (br s, 1H), 7.65 (m, 2H), 7.48 (m, 2H), 7.43 (m, 2H), 7.23 (d, 1H), 6.38 (br s, 1H), 4.46 (s, 2H), 3.87 (s, 2H), 3.53 (m, 2H), 3.50 (d, 1H), 3.40 (d, 1H), 3.00 (m, 2H) and 1.46 (s, 3H) ppm.
Example 4 (SS)-S-Methyl-5-{F(6-pyridin-3-yl-3,4-dih droisoquinolin-2(1H)-yl)sulfonLl]methyl} imidazolidine-2,4-dione N~ o i,0 N
u O
O ~
White solid.
LC-MS na/z 401 (M+l);

1H NMR (CD3CN) S 8.98 (br s, 1H), 8.71 (m, 1H), 8.54 (d, 2H), 7.89 (m, 1H), 7.56 (m, 2H), 7.34 (m, 1H), 6.34 (br s, 1H), 4.49 (s, 2H), 3.55 (m, 2H), 3.52 (d, 1H), 3.41 (d, 1H), 3.03 (m, 2H) and 1.47 (s, 3H) pp.in.

The starting material was prepared as follows:

(5S)-5-(f [6-Bromo-3,4-dihydroisoquinolin-2(1ffi-yl]sulfon l}methyl)-5-methylimidazolidine-2,4-dione A 3:1 rnixture (0.44 g, 1.4 mmol) of 6-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline and 8-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline (prepared according to Tetrahedron Lett. 1996, 37(31), 5453-5456) was stirred in ethanol (10 mL) containing a few drops of 25% ammonium hydroxide at RT. After 2.5 h, the solution was concentrated, dissolved in dry THF (1.0 mL) under argon and cooled on an ice-bath. DIPEA (0.41 mL, 2.4 mmol) was added followed by a solution of [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl-chloride-(0.-27-g, 4:2 mmol)-and-dry THF (1.0 -mL). The mixture was stirred at RT for 1 h and then concentrated. The crude product was taken up in water and extracted twice with EtOAc. The combined organic phases were washed with brine, dried, filtered and concentrated to give 0.55 g of a mixture of (5,S)-5-( { [6-bromo-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione and (5S)-5-({[8-bromo-3,4-dihydroisoquinolin-2(lH)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione. The regioisomers were separated by preparative HPLC.
(5S)-5-({[8-Bromo-3,4-dih droisoquinolin-2(1.H)-yl]sulfon 1}methyl)-5-methylimidazolidine-2,4-dione (eluting first) Yield: 0.13 g of a white solid.
LC-MS nalz 402/404 (M+1), 419/421 (M+18);

1H NMR (CD3CN) 8 8.48 (br s, 1H), 7.48 (m, 1H), 7.21 (m, 1H), 7.14 (m, 1H), 6.31 (br s, 1H), 4.36 (s, 2H), 3.48 (m, 4H), 2.95 (m, 2H) and 1.46 (s, 314) ppm.

(5S)-5-( f f6-BroYno-3,4-dih droquinolin-2(1H)-yllsulfonyl}meth 1~
methylimidazolidine-2,4-dione (eluting second) 1s Yield: 0.25 g of a white solid.
LC-MS m/z 402/404 (M+1), 419/421 (M+18);

I H NMR (CD3CN) S 8.47 (br s, 1H), 7.38 (m, 1H), 7.36 (m, 1H), 7.08 (m, 1H), 6.29 (br s, 1H), 4.36 (s, 2H), 3.48 (m, 2H), 3.47 (d, 1H), 3.37 (d, 1H), 2.92 (m, 2H) and 1.45 (s, 3H) ppm.

Example 5 (5,S)-5- {[6-(4-Chlorophenyl)-3,4-dihydro-2,7-naphthyridin-2(1H)_ yl] sulfonyl } methyl)-5 -methylimidazolidine-2, 4-dione ci /
o Nz~
N i0 ~
.,.~~ H
O O
[(4,S')-4-Methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.086 g, 0.38 mmol) in-anhydrous NMP-(0:50 -mL-)-was added-dropwise to-a stirred-solution of-6-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,7-naphthyridine (0.046 g, 0.19 rnmol), DIPEA (0.066 mL, 0.38 minol) and anhydrous NMP (1.5 mL) at RT. After the addition was complete the solution was stirred at RT for 1.5 h, then diluted with water (1 mL) and purified by preparative HPLC to afford 0.0070 g (8%) of the title compound as a white solid.
LC-MS rn/z 435, 436 (M+1);

iH NMR (DMSO-d6) 8 10.8 (s, 1H), 8.49 (s, 1H), 8.10 (d, 2H), 8.06 (s, 1H), 7.84 (s, 1H), 7.54 (d, 2H), 4.45 (s, 2H), 3.61 (d, 1H), 3.48 (d, 1H), 3.47 (t, 2H), 2.98 (t, 2H) and 1.34 (s, 3H) ppm.

The starting materials were prepared as follows:
6-(4-Chlorophenyl)-1,2,3,4-tetrahydro-2,7-naphthridine tert-Butyl 6- { [(trifluoromethyl)sulfonyl]oxy} -3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (0.69 g, 1.8 mmol), 4-chlorophenylboronic acid (0.39 g, 2.5 mmol), PdC12 x dppf (0.050 g), saturated sodium carbonate (2 mL), EtOH (4 mL) and toluene (4 mL) were stirred at 80 C for 6 h. The solution was cooled to RT, talcen up in water (10 mL) and extracted with EtOAc (25 mL). The combined organic phases were washed with brine, dried, filtered and concen.trated. Purification by column chromatography with EtOAc-heptanes (1:1) as eluent gave 0.065 g (10%) of tert-butyl6-(4-chlorophenyl)-3,4-dihydro-2,7-naphthyridine-2(1R)-carboxylate.
LC-MS nilz 345 (M+l).
This material was dissolved in MeOH (2 mL) and acetyl chloride (0.2 mL) was slowly added. After stirring at 40 C overnight, the solution was concentrated, the residue was taken up in 1 M sodium hydroxide (10 mL) and extracted with EtOAc-ether (1:1) (4 x 30 mL). The combined organic phases were dried, filtered and concentrated to give 0.046 g (100%) of the crude title compound.
LC-MS mlz 245 (M+1).

tert-Butyl 6-{[(trifluoromethyl)sulfonyl]oxY -3,4-dihydro-2,7-naphthyridine-2(1H)---'30---- -carboxylate-Crude 3-methoxy-2,7-naphthyridine (prepared from 4.4 mmol of 6-methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde) was hydrogenated (30 psi pressure) at RT over Pt02 (approx. 0.1 g) in HOAc (25 mL) for 2.5 h. The solution was filtered through a Celite pad and the clear filtrate was concentrated by freeze-diying to give crude 6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine as the acetate salt.
LC-MS fnlz 165 (M+1).
This material was refluxed in 48% hydrobromic acid for 10 h. The volatiles were evaporated and the residue was dried under vacuum and 45 C to give approx.
0.70 g. of crude 5,6,7,8-tetrahydro-2,7-naphthyridin-3-ol hydrobromide.
LC-MS rnlz 151 (M+1).
This material (approx. 4.8 mmol) was dissolved in water (13 mL) and treated with TEF
(33 inL), Et3N (0.85 mL, 6.0 mmol) and BOC-anhydride (1.6 g, 7.3 mmol) at RT.
After stiiTing at the same temperature for 6 h the solution was concentrated to one third of its original volume and the residue was taken up in water and extracted three times with EtOAc. The combined organic phases were dried, filtered and concentrated to give 0.80 g (67% crude yield) of tert-butyl6-hydroxy-3,4-dihydro-2,7-naphthyridine-2(111)-i5 carboxylate as a white solid.
LC-MS mlz 251 (M+1), 195 (M-55).
This material (approx. 5.4 mmol) was dissolved in a two-phase system of toluene (20 mL) and 30% aqueous tripotassium orthophosphate (20 mL) and treated with triflic anhydride (1.6 mL, 6.8 mniol) at 4 C [Org. Lett. 2002, 4(26), 4717-4718]. The ice-bath was removed and the stirring was continued for 2 h at RT after which the two phases were separated.
The aqueous phase was washed once with toluene. The combined organic phases were washed with brine, dried and concentrated. Purification by column chromatography with EtOAc-heptanes (2:1) as eluent gave 0.45 g (17 % yield) of the title product.
LC-MS rnlz 383 (M+1), 283 (M-99).
3-Methox -~2,7-naphthyridine To a stirred solution ofN,N,N'-trimethylethylenediamine (1.9 mL, 15 mmol) in anhydrous THF (65 mL) under argon at -70 C was slowly added 1.6M n-BuLi in hexanes (9.0 mL, 14 mmol). After stirring at -70 C for 15 minutes, 6-methoxy-nicotinaldehyde (1.3 g, 9.8 _,. _30__ _mmol)_was-added-dr~opwise-After_the_addition_was_complete,-stirring-was-e.ontinued_at_ -70 C for another 15 minutes. Then 1.6M n-BuLi in hexanes (10 mL, 16 mmol) was added dropwise and stirring continued at -45 C for 4 h. The solution was cooled to -70 C and then a solution of iodine (3.0 g, 12 mmol) and anhydrous THF (25 mL) was added dropwise. When the addition was complete, stirring was continued at -70 C for 30 minutes and then at RT for 3 h. The crude product was talcen up in ether (40 mL) and washed successively with saturated ammonium chloride (2 x 40 mL) and 5% sodium 5 thiosulfate (2 x 20 mL). The organic phase was dried, filtered and concentrated.
Purification by column chromatography with EtOAc-heptanes (1:1) as eluent gave 0.41 g (15% yield) of 4-iodo-6-methoxynicotinaldehyde.
LC-MS rnlz 264 (M+1);

1H NMR (CDC13) 8 9.95 (s, 1H), 8.53 (s, 1H), 7.32 (s, 1H) and 3.98 (s, 3H) ppm.
4-lodo-6-methoxynicotinaldehyde (0.41 g, 1.6 nunol), trimethylsilylacetylene (0.35 mL, 2.8 mmol), PdCl2(PPh3)Z (catalytic amount), CuI (catalytic amount), TEA (2 mL) and THF
(10 mL) were stirred at 60 C for 2 h. The volatiles were evaporated and the residue was taken up in water and extracted with ether. The organic phase was dried, filtered and concentrated. Purification by column chromatography with EtOAc-heptanes (1:3) as eluent gave 0.25 g (68% yield) of 6-methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde.
LC-MS m/z 234 (M+1);

H NMR (CDC13) 8 10.4 (s, 1H), 8.73 (s, 1H), 6.84 (s, 1H), 4.03 (s, 3H) and 0.30 (s, 9H) ppm.

6-Methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde (0.25 g, 1.1 mmol) and 7M
ammonia in MeOH (5 mL) were stirred in a sealed vial at 80 C overnight. The solution was concentrated, taken up in saturated sodium carbonate and extracted with ether. The organic phase was dried, filtered and concentrated to give 0.20 g of the title product.
GC-MS nalz 160 (M);

iH NMR (CDC13) b 9.41 (s, 1H), 9.27 (s, 1H), 8.47 (d, 1H), 7.64 (d, 1H), 7.03 (s, 1H) and 4:12 (s, 3H) ppm.

Pharmacoloaical Examnle Isolated Enzyme AssEs Recombinant human MMP12 catalytic domain may be expressed and purified as described by Parkar A.A. et al, (2000), Protein Expression and Purification, 20 152. The purified enzyme can be used to monitor inhibitors of activity as follows: MMP12 (50 ng/ml final concentration) is incubated for 60 minutes at room temperature with the synthetic substrate Mca-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2 (10 M) in assay buffer (0.1M "Tris-HCl"
(trade marlc) buffer, pH 7.3 containing 0.1M NaCl, 20mM CaClz, 0.020 mM ZnCI
and 0.05% (w/v) "Brij 35" (trade mark) detergent) in the presence (10 concentrations) or absence of inhibitors. Activity is determined by measuring the fluorescence at kex 320 nm and kem 405 nm. Percent inhibition is calculated as follows:

% Inhibition is equal to the [Fluorescenceplus inhibitor -Fluorescencebackgf=ound] divided by the [Fluorescenceninus inhibitor - Fluorescencebackgroundl=

Purified pro-MMP8 is purchased from Calbiochem. The enzyme (at 10 g/ml) is activated by p-amino-phenyl==mercuric acetate (APMA) at 1 mM for 2.5 h, 35 C. The activated enzyme can be used to monitor inhibitors of activity as follows: MMP8 (200 ng/ml final concentration) is incubated for 90 minutes at 35 C (80% H20) with the synthetic substrate Mca-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2 (12.5 M) in assay buffer (0.1M "Tris-HCl"
(trade marlc) buffer, pH 7.5 containing 0.1M NaCI, 30mM CaC12, 0.040 mM ZnCI
and 0.05% (w/v) "Brij 35" (trade mark) detergent) in the presence (10 concentrations) or absence of inhibitors. Activity is determined by measuring the fluorescence at kex 320 nm and kem 405 nm. Percent inhibition is calculated as follows:

% Inhibition is equal to the [Fluorescenceplus inhibitor -Fluorescencebackgf=ound] divided by the [Fluorescenceminus inhibitor- Fluorescencebackgroundl=

Recombinant human MMP9 catalytic domain was expressed and then purified by Zn chelate column chromatography followed by hydroxamate affinity column chromatography. The enzyme can be used to monitor inhibitors of activity as follows:
MMP9 (5 ng/inl final concentration) is incubated for 30 minutes at RT with the synthetic substrate Mca-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2 (5 M) in assay buffer (0.1M
"Tris-HCI" (trade marlc) buffer, pH 7.3 containing 0.1M NaCl, 20mM CaCh, 0.020 mM
ZnCI
and 0.05% (w/v) "Brij 35" (trade marlc) detergent) in the presence (10 concentrations) or absence of inhibitors. Activity is determined by measuring the fluorescence at kex 320 nm.
and kem 405 mn. Percent inhibition is calculated as follows:

% Inhibition is equal to the [Fluorescenceplus inhibitor -Fluorescencebackground] divided by the [Fluorescence,,,inus inhibitoi - Fluorescencebackgroundl=

Recombinant human MMP14 catalytic domain may be expressed and purified as described by Parkar A.A. et al, (2000), Protein Expression and Purification, 20 152. The purified enzyme can be used to monitor inhibitors of activity as follows: M1VIP14 (10 ng/ml final concentration) is incubated for 60 minutes at room temperature with the synthetic substrate Mca-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2 (10 M) in assay buffer (0.1M "Tris-HCl"

(trade mark) buffer, pH 7.5 containing 0.1M NaCl, 20mM CaC12, 0.020 mM ZnCl and 0.05% (w/v) "Brij 35" (trade mark) detergent) in the presence (5 concentrations) or absence of inhibitors. Activity is determined by measuring the fluorescence at kex 320 nm and kem 405 nm. Percent inhibition is calculated as follows: % Inhibition is equal to the [Fluorescenceplus inlzibitor - Fluorescencebackground] divided by the [FluorescenceõZinus inhibitor - Fluorescencebackground]=

A protocol for testing against other matrix metalloproteinases, including MMP9, using expressed and purified pro MMP is described, for instance, by C. Graham Knight et al.
z (1992) FEBS Lett., 296(3), 263-266.

Recombinant human MMP19 catalytic domain may be expressed and purified as described by Parkar A.A. et al, (2000), Protein Expression and Purification, 20:152. The purified enzyme can be used to monitor inhibitors of activity as follows: MMP 19 (40 ng/n-A final concentration) is incubated for 120 minutes at 35 C with the synthetic substrate Mca-Pro-Leu-Ala-Nva-Dpa-Ala-Arg-NH2 (5 M) in assay buffer (0.1M "Tris-HCl" (trade inarlc) buffer, pH 7.3 containing 0.1M NaCI, 20mM CaC12, 0.020 mM ZnCI and 0.05% (w/v) "Brij 35" (trade mark) detergent) in the presence (5 concentrations) or absence of inhibitors. Activity is determined by measuring the fluorescence at kex 320 nm and kem 405 nm. Percent inhibition is calculated as follows: % lnhibition is equal to the [Fluorescenceplus inhibitor= - Fluorescencebackground] divided by the [Fluorescencenzinus inhibitor- Fluorescencebackgrourzdl-1s The following table shows data for a representative selection of the compounds of the present invention.

Table hMMP12 hMMP9 hMMP14 Compound TCso (01) TCso (nM) ICso (nM) Example 1 10.4 29.3 > 10000 Examp] e 2 1.4 3.5 415 Example 5 7 8.3 1990

Claims (15)

1. A compound of formula (1) or a pharmaceutically acceptable salt thereof wherein R1 represents H, halogen, CF3 or CH2CN;
R2 represents C1 to 3 alkyl; and A, A1 and B each independently represent CH or N;

2. A compound according to Claim 1, wherein R1 represents chloro.

3. A compound according to Claim 1, wherein R1 represents CF3.

4. A compound according to any one of Claims 1 to 3, wherein R2 represents methyl or ethyl.

5. A compound according to any one of Claims 1 to 4, wherein A and A1 each represent N.

6. A compound according to Claim 1 which is selected from the group consisting of:
(5S)-5-methyl-5-({[6-[2-(trifluoromethyl)pyrimidin-5-yl]-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;
(5S)-5-({[6-(4-chlorophenyl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)-methylimidazolidine-2,4-dione;
{4-[2-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]phenyl}acetonitrile;
(5S)-5-methyl-5-{[(6-pyridin-3-yl-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}imidazolidine-2,4-dione;
(5S)-5-({[6-(4-chlorophenyl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;
and pharmaceutically acceptable salts thereof.

7. A process for the preparation of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof which comprises:
a) reaction of a compound of formula (II) wherein R2 is as defined in formula (I) and L1 represents a leaving group, with a compound of formula (III) (or a salt thereof) wherein R1, A, A1 and B are as defined in formula (I); or b) reaction of a compound of formula (V) wherein R2 and B are as defined in formula (I) and LG is a leaving group; with a boronic acid derivative of formula (XII) wherein R1, A and A1 are as defined in formula (I); or c) reaction of a compound of formula (IX) wherein R1, R2, A, A1 and B are as defined in formula (I); with ammonium carbonate and potassium cyanide;
and optionally thereafter forming a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

9. A process for the preparation of a pharmaceutical composition as claimed in claim 8 which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 6 with a pharmaceutically acceptable adjuvant, diluent or carrier.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6 for use in therapy.

11. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use in the treatment of an obstructive airways disease.

12. Use according to claim 11, wherein the obstructive airways disease is asthma or chronic obstructive pulmonary disease.

13. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, osteoarthritis, atherosclerosis, cancer or multiple sclerosis.

14. A method of treating a disease or condition mediated by MMP12 and/or MMP9 which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6.

15. A method of treating an obstructive airways disease which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6.